Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis.
Cell Host Microbe
; 29(6): 941-958.e10, 2021 06 09.
Article
in En
| MEDLINE
| ID: mdl-33989515
ABSTRACT
Infection with CagA-producing Helicobacter pylori plays a causative role in the development of gastric cancer. Upon delivery into gastric epithelial cells, CagA deregulates prooncogenic phosphatase SHP2 while inhibiting polarity-regulating kinase PAR1b through complex formation. Here, we show that CagA/PAR1b interaction subverts nuclear translocation of BRCA1 by inhibiting PAR1b-mediated BRCA1 phosphorylation. It hereby induces BRCAness that promotes DNA double-strand breaks (DSBs) while disabling error-free homologous recombination-mediated DNA repair. The CagA/PAR1b interaction also stimulates Hippo signaling that circumvents apoptosis of DNA-damaged cells, giving cells time to repair DSBs through error-prone mechanisms. The DSB-activated p53-p21Cip1 axis inhibits proliferation of CagA-delivered cells, but the inhibition can be overcome by p53 inactivation. Indeed, sequential pulses of CagA in TP53-mutant cells drove somatic mutation with BRCAness-associated genetic signatures. Expansion of CagA-delivered cells with BRCAness-mediated genome instability, from which CagA-independent cancer-predisposing cells arise, provides a plausible "hit-and-run mechanism" of H. pylori CagA for gastric carcinogenesis.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Bacterial Proteins
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Helicobacter pylori
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Helicobacter Infections
/
BRCA1 Protein
/
Genomic Instability
/
Epithelial Cells
/
Antigens, Bacterial
Limits:
Adult
/
Aged
/
Aged80
/
Animals
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Year:
2021
Type:
Article